Manufacture of optically active menthols



Patented Feb. 27, 1934.-

FFECE MANUFACTURE OF @PTICALLY ACTEVE MENTHGLS John Read, St. Andrews, and William John Grubb, Anstruther Waste-r, Scotland Application February 21, 1833, in Great Britain March No Drawing.

Serial No. 657,922, and 4, 1932 1 Claims. (Cl. 269-453) Whilst racemic menthol has been resolved into its optically active constituents, the methods hitherto used have been laborious or have provided only small yields of the optically active substances (Journal of the Chemical Society, 1912, page 109 et seq; 1931, page 138).

This invention provides a simpler and more rapid and economical process for obtaining dextro-menthol or leave-menthol or both from tures thereof (including raceinic menthol and mixtures of racemic menthol with an optically active menthol). The process of the invention comprises converting the menthols into esters of an optically active menthoxy-acetic acid (leave or dextro) and iractionally crystallizing the mixture of esters so obtained. ite use or the laevo-acid leads to the production of the dextro-menthol, while the use of the dextro-acid leads to the production of the ltevo-roenthol. For example, where the lave-acid is employed for the conversion of the menthols into their esters by fractionally crystallizing the resulting esters from one of the usual organic solvents, such as methyl alcohol, there can be obtained the pure deXtro-menthol ester which on hydrolysis under suitable conditions yields pure dextro-menthol.

The optically active menthol of opposite direction of optical rotation (in the case of the example given above, lavo menthol) can be recovered from the mother liquors oi the fractional crystallization by decomposing the esters remaining in the mother liquors, converting the liberated menthols into their esters of an optically active menthoxy-acetic acid whose direction of optical rotation is opposite to that of the acid Whose esters were formed in the initial stage of the process, and fractionally crystallizing the esters so as to obtain a pure ester which on hydrolysis under suitable conditions yields the pure optically active menthol (in the case of the example given above, lavo menthol). The esters remaining in the mother liquors may be decomposed and the liberated menthols recovered and subjected again to the process.

Similarly, by treating the initial mixture or dextroand lzevmmenthols with dextro-inenthoxy-acetic acid, a mixture or" the dextroand lave-menthol esters of the dextro-acid may be obtained, from which the pure leave-men hol ester may be isolated by fractional crystallization, which lave-menthol ester on hydrolysis under suitable conditions yields pure lzevo-menthol. From the menthols recovered from the mother liquors remaining after fractional crystallization, the dextro-menthol may be isolated by the use of lavo-menthoxy-acetic acid to produce the esters of the leevo-acid.

It is to be noted that menthoxy-acetic acid is itself capable of being decomposed by hydrolysis into menthol and acetic acid; hence for liberating the pure optically active menthols from their esters of menthoxy-acetic acid, care must be taken to avoid conditions of hydrolysis which would cause decomposition also of the menthoxyacetic acid liberated in the course of the hydroly- A suitable procedure for obtaining the optically active menthols from the esters consists in heating the esters with a dilute alcoholic alkali solution, say a solution of about 1 per cent. strength.

The menthoxy-acetic acid may be recovered and used again in the process.

The invention permits the isolation, in a simple and economical manner, and in good yield, of substantially pure dextro-menthol and laevomenthol. The pure products melt at 42-43" C. and have the odor and taste of the naturally occurring menthol.

The optically active menthoxy-acetic acids used in carrying out the invention may be made, for example, in the manner described in the Journal of the Chemical Society, 1931,pages1932- 1934; or an optically inactive menthoxy-acetic acid may be prepared from inactive menthol and resolved by any known method.

The menthol esters of the optically active menthoxy-acetic acids may be made by one of the usual methods of esterification, for instance, by reaction of the mixture of optically active nienthols with an optically active menthoxyacetyl chloride in presence of a tertiary base, such as pyridine or quinoline.

The following examples illustrate the invention:-

Example L-ifi grams of racemic menthol are treated in solution in pyridine with the crude lavo-menthoxy-acetyl chloride made by heating 215 grams of lavo-inenthoxy-acetic acid with thicnyl chloride, whereby there were obtained 312.? grams of the crude racemic menthol ester of lavo-rnenthoxy-aoetic acid. 297 grams of this ester were recrystallized eight times from methyl alcohol and yielded 67 grams of the pure dextromenthyl ester of leevo-nienthoxy-acetic acid corresponding with a yield of per cent. of heory. By hydrolysis oi this ester by means of dilute alcoholic potash of about 1 per cent. strength, there was obtained, in a yield oi 83.5

per cent. of the theory, dextro-menthol having a melting point of 42-43" 0., a boiling point of 99 C. at 12.5 mm pressure and an optical rotation in alcoholic solution Example 2.'Ihe methyl alcoholic mother liquors of the recrystallizations described in Example l were treated in order to decompose the ester and recover the liberated menthol. 29 grams of the recovered menthol [z J= were esterified by treatment with the theoretical quantity of dextro-menthoxy-acetyl chloride in pyridine, and the ester formed was isolated and recrystallized four times from methyl alcohol, whereby there was obtained the pure laevomenthol ester of dextro-menthoxy-acetic acid By saponifying the ester by means of dilute alcoholic potash of about 1 per cent. strength there was obtained a pure laevo-menthol having properties identical with those of the naturally occurring product, namely melting point=42-43 C., boiling point=93 C., under a pressure of 10 mm., and

The mother liquors may be again worked up for recovery of the menthol and the recovered menthol may be treated again by the process of Example 1 or Example 2.

Having thus fully described the nature of the said invention and the best means we know of carrying the same into practical effect, what we claim as our invention is:-

l. A manufacture of an optically active menthol, which comprises converting a mixture of dextro-menthol and laevo-menthol into their esters of an optically active menthoxy-acetic acid, isolating one of the esters by fractional crystallization of the mixture of esters and hydrolyzing the isolated ester under conditions under which the menthoxy-acetic acid liberated during the hydrolysis is not decomposed.

2. A manufacture of an optically active menthol, which comprises decomposing the esters contained in the mother liquors of the crystallization referred to in claim 1, converting the liberated menthols into esters of an optically active menthoxy-acetic acid whose direction of optical rotation is opposite to that of the optically active menthoxy-acetic acid referred to in claim 1, isolating one of the esters by fractional crystallization of the mixture of esters thus obtained and hydrolyzing the isolated ester under conditions under which the menthoxy-acetic acid liberated during the hydrolysis is not decomposed.

3. A manufacture of dextro-menthol, which comprises converting a mixture of dextro-menthol and leave-menthol into their esters of lzevomenthoxy-acetic acid, isolating the dextro-menthol ester by fractional crystallization of the mixture of esters and hydrolyzing the isolated ester under conditions under which the menthoxyacetic acid liberated during the hydrolysis is not decomposed.

4. A manufacture of laevo-menthol, which comprises decomposing the esters contained in the mother liquors of the crystallization referred to in claim 3, converting the liberated menthols into esters of dextro-menthoxy-acetic acid, isolating the lavo-menthol ester by fractional crystallization of the mixture of esters and hydrolyzing the isolated ester under conditions under which the menthoxy-acetic acid liberated during the hydrolysis is not decomposed.

5. A manufacture of an optically active menthol which comprises converting a mixture of dextromenthol and laevo-menthol into their esters of an optically active menthoxy-acetic acid, isolating one of the esters by fractional crystallization of the mixture of esters and hydrolyzing the isolated ester by means of a dilute alcoholic solution of an alkali.

6. A manufacture of an optically active menthol, which comprises decomposing the esters contained in the mother liquors of the crystallization referred to in claim 5, converting the liberated menthols into esters of an optically active menthoxy-acetic acid whose direction of optical rotation is opposite to that of the optically active menthoxy-acetic acid referred to in claim 5, isolating one of the esters by fractional crystallization of the mixture of esters thus obtained and hydrolyzing the isolated ester by means of a dilute alcoholic solution of an alkali.

7. A manufacture of dextro-nenthol, which 100 comprises converting a mixture of deXtro-menthol and laevo-menthol into their esters of lavamenthoxy-acetic acid, isolating the dextro-menthol ester by fractional crystallization of the mixture of esters and hydrolyzing the isolated ester by means of a dilute alcoholic solution of an alkali.

8. A manufacture of lave-menthol, which comprises decomposing the esters contained in the mother liquors of the crystallization referred to in claim 7, converting the liberated menthols into esters of dextro-menthoxy-acetic acid, isolating the lavo-menthol ester by fractional crystallization of "the mixture of esters and hydrolyzing the isolated ester by means of a dilute alcoholic solution of an alkali.

9. A process for the isolation of optically active menthols from a mixture of dextro-menthol and leave-menthol, which comprises converting said mixture into their esters of an optically active menthoxy-acetic acid, fractionally crystallizing the mixture of esters to isolate one of the esters, and hydrolyzing the isolated ester under conditions under which the menthoxy-acetic acid lib erated during the hydrolysis is not decomposed.

10. A process for the isolation of optically active menthols from a mixture of dextro-menthol and laevo-menthol, which comprises converting said mixture into their esters of an optically active menthoxy-acetic acid, fractionally crystallizing the mixture of esters to isolate one of the esters, hydrolyzing the isolated ester under conditions under which the menthoxy-acetic acid liberated during the hydrolysis is not decomposed, then decomposing the esters contained in the said 135 mother liquors of crystallization remaining after the isolation of the first mentioned esters, converting the menthols liberated by such decomposition into esters of an optically active menthoxy-acetic acid whose direction of optical rotation is opposite to that of the first mentioned optically active menthoxy-acetic acid, fractionally crystallizing the mixture of esters thus obtained to isolate one of the esters, and hydrolyzing the isolated ester under conditions under 145 which the menthoxy-acetic acid liberated during the hydrolysis is not decomposed.

JOHN READ. WILLIAM JOHN GRUBB. 

